Polymer-tissue hybrid biomaterials and methods of making and using same

Abstract

Provided are hybrid biomaterials comprising one or more layers of cross-linked poly(propylene fumarate) and/or cross-linked copolymer comprising a plurality of cross-linked propylene fumarate moieties. The layers may further comprise a plurality of microparticles, a plurality of micropores, or both a plurality of microparticles and a plurality of micropores encapsulated within the cross-linked poly(propylene fumarate) and/or cross-linked copolymer comprising a plurality of cross-linked propylene fumarate moieties. One of the layers is disposed on a compliant matrix dense tissue substrate (e.g., a pericardium tissue substrate). The hybrid biomaterials can be used, for example, in method of repairing tissue defects.

The invention claimed is: 
     
       1. A hybrid biomaterial comprising:
 a) a compliant matrix dense tissue substrate; 
 b) a first PPF layer comprising cross-linked poly(propylene fumarate) and/or cross-linked copolymer comprising a plurality of cross-linked propylene fumarate moieties; and 
 c) a second PPF layer comprising cross-linked poly(propylene fumarate) and/or cross-linked copolymer comprising a plurality of cross-linked propylene fumarate moieties and a plurality of microparticles, a plurality of micropores, or both a plurality of microparticles and a plurality of micropores encapsulated within the cross-linked poly(propylene fumarate) and/or cross-linked copolymer comprising a plurality of cross-linked propylene fumarate moieties; 
 
       wherein, 
       the first PPF layer is disposed on at least a portion of a surface of the tissue substrate and the second PPF layer is disposed on at least a portion of a surface of the first PPF layer, or the second PPF layer is disposed on at least a portion of a surface of the tissue substrate and the first PPF layer is disposed on at least a portion of a surface of the second PPF layer. 
     
     
       2. The hybrid biomaterial of  claim 1 , wherein the cross-linked poly(propylene fumarate) or copolymer comprising a plurality of cross-linked propylene fumarate moieties comprise a plurality of diethylfumarate (DEF) cross-linking moieties, N-vinylpyrollidone cross-linking moieties, or a combination of diethylfumarate cross-linking moieties and N-vinylpyrollidone cross-linking moieties. 
     
     
       3. The hybrid biomaterial of  claim 1 , wherein the microparticles comprise poly(lactic-co-glycolic acid), poly(ethylene glycol), alginate, gelatin, collagen, poly(ethylene glycol), or a combination thereof. 
     
     
       4. The hybrid biomaterial of  claim 1 , wherein the microparticles are 50 weight percent to 95 weight percent of the second PPF layer. 
     
     
       5. The hybrid biomaterial of  claim 1 , wherein the microparticles comprise a bioactive material. 
     
     
       6. The hybrid biomaterial of  claim 5 , wherein the bioactive material is selected from an antibiotic material, a cytokine, a growth factor, immunosuppressant material, and combinations thereof. 
     
     
       7. The hybrid biomaterial of  claim 1 , wherein the second PPF layer further comprises a surfactant and the surfactant forms a layer at least partially disposed on a portion of a surface of one or more of the microparticles. 
     
     
       8. The hybrid biomaterial of  claim 7 , wherein the surfactant is selected from polyvinyl alcohol, vitamin E, 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), N-(Carbonyl-methoxypolyethyleneglycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG), and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and combinations thereof. 
     
     
       9. The hybrid biomaterial of  claim 1 , wherein the compliant matrix dense tissue substrate has a thickness of 300 micrometers to 1 millimeter and/or an area of 1,000 mm 2  to 1,000 cm 2 . 
     
     
       10. The hybrid biomaterial of  claim 1 , wherein the first PPF layer and/or second PPF layer has a thickness of 25 micrometers to 1 millimeter and/or an area of 1,000 mm 2  to 1,000 cm 2 . 
     
     
       11. The hybrid biomaterial of  claim 1 , wherein the poly(propylene fumarate) has a molecular weight of 500 to 4,000 g/mol. 
     
     
       12. A method of making the hybrid biomaterial of  claim 1 , comprising:
 a) providing an alcohol-dehydrated compliant matrix dense tissue substrate; 
 b) coating at least a portion of the substrate with a first mixture comprising poly(propylene fumarate) or copolymer comprising a plurality of propylene fumarate moieties, a cross-linking agent, a photoinitiator, and a plurality of microparticles or a second mixture comprising poly(propylene fumarate) or copolymer comprising a plurality of propylene fumarate moieties, a cross-linking agent, and a photoinititor; 
 c) exposing the coated substrate from b) to ultraviolet light such that the poly(propylene fumarate) or copolymer comprising a plurality of propylene fumarate moieties is crosslinked, 
 d) if the first mixture is used in b), then coating the substrate from c) with the second mixture, 
 e) exposing the coated substrate from d) to ultraviolet light such that the poly(propylene fumarate) or copolymer comprising a plurality of propylene fumarate moieties is crosslinked to provide the hybrid biomaterial, 
 f) if the second mixture is used in b), then coating the substrate from c) with the first mixture, and 
 g) exposing the coated substrate from d) to ultraviolet light such that the poly(propylene fumarate) or copolymer comprising a plurality of propylene fumarate moieties is crosslinked to provide the hybrid biomaterial. 
 
     
     
       13. The method of  claim 12 , further comprising the steps of:
 h) coating at least a portion of the product of g) with a first mixture comprising poly(propylene fumarate) or copolymer comprising a plurality of propylene fumarate moieties, a cross-linking agent, a photoinitiator, and a plurality of microparticles or a second mixture comprising poly(propylene fumarate) or copolymer comprising a plurality of propylene fumarate moieties, a cross-linking agent, and a photoinititor; 
 i) exposing the coated substrate from h) to ultraviolet light such that the poly(propylene fumarate) or copolymer comprising a plurality of propylene fumarate moieties is crosslinked, 
 j) if the first mixture is used in h), then coating the substrate from i) with the second mixture, 
 k) exposing the coated substrate from j) to ultraviolet light such that the poly(propylene fumarate) or copolymer comprising a plurality of propylene fumarate moieties is crosslinked to provide the hybrid biomaterial, 
 l) if the second mixture is used in h), then coating the substrate from i) with the first mixture, and 
 m) exposing the coated substrate from j) to ultraviolet light such that the poly(propylene fumarate) or copolymer comprising a plurality of propylene fumarate moieties is crosslinked to provide the hybrid biomaterial; 
 n) optionally, repeating steps h-n to provide additional layers to the substrate. 
 
     
     
       14. The method of making the hybrid biomaterial of  claim 12 , wherein the cross-linking agent is selected from diethylfumarate (DEF), N-vinylpyrrolidone, and combinations thereof. 
     
     
       15. The method of making the hybrid biomaterial of  claim 12 , further comprising removal of one or more of the microparticles from the hybrid biomaterial. 
     
     
       16. A method for repairing a tissue defect in an individual comprising implanting in a region of the individual a hybrid biomaterial comprising:
 a) a compliant matrix dense tissue substrate; 
 b) first PPF layer comprising cross-linked poly(propylene fumarate) and/or cross-linked copolymer comprising a plurality of cross-linked propylene fumarate moieties, and 
 c) a second PPF layer comprising cross-linked poly(propylene fumarate) and/or cross-linked copolymer comprising a plurality of cross-linked propylene fumarate moieties and a plurality of microparticles, a plurality of micropores, or both a plurality of microparticles and a plurality of micropores encapsulated within the cross-linked poly(propylene fumarate) and/or cross-linked copolymer comprising a plurality of cross-linked propylene fumarate moieties, wherein the hybrid biomaterial is less immunogenic than a reference material, and 
 wherein the first PPF layer is disposed on at least a portion of a surface of the tissue substrate and the second PPF layer is disposed at least a portion of a surface of the first layer, or 
 the second PPF layer is disposed on at least a portion of a surface of the tissue substrate and the first PPF layer is disposed on at least a portion of a surface of the second layer. 
 
     
     
       17. The method for repairing a tissue defect in an individual of  claim 16 , wherein the microparticles comprise a bioactive material and the bioactive material is released into the individual. 
     
     
       18. The method for repairing a tissue defect in an individual of  claim 17 , wherein the bioactive material is selected from an antibiotic material, a cytokine, a growth factor, immunosuppressant material, and combinations thereof.